Diabetes is caused by multiple factors and is characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state. There are two generally recognized forms of diabetes: Type I diabetes, or insulin dependent diabetes, in which patients produce little or no insulin and Type II diabetes, or noninsulin-dependent diabetes wherein patients produce insulin, while at the same time demonstrating hyperglycemia. Type I diabetes is typically treated with exogenous insulin administered via injection. However, Type II diabetics often present “insulin resistance”, such that the effect of insulin in stimulating glucose and lipid metabolism in the main insulin-sensitive tissues, namely muscle, liver and adipose tissues, is diminished and hyperglycemia results.
Persistent or uncontrolled hyperglycemia that occurs in diabetes is associated with increased morbidity and premature mortality. Abnormal glucose homeostasis is also associated, both directly and indirectly, with obesity, hypertension and alterations in lipid, lipoprotein and apolipoprotein metabolism. Type II diabetics are at increased risk of cardiovascular complications such as atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, retinopathy and also neuropathy. Many patients who have insulin resistance, but have not developed Type II diabetes, are also at risk of developing symptoms referred to as “Syndrome X”, or “Metabolic Syndrome”. Metabolic syndrome is characterized by insulin resistance, along with abdominal obesity, hyperinsulinemia, high blood pressure, low HDL (high density lipoproteins) and high VLDL (very low density lipoprotein), hypertriglyceridemia and hyperuricemia. Whether or not they develop overt diabetes, these patients are at increased risk of developing cardiovascular complications.
Current treatments for diabetes include: insulin, insulin secretagogues, such as sulphonylureas, which increase insulin production from pancreatic β-cells; glucose-lowering effectors, such as metformin which reduce glucose production from the liver; activators of the peroxisome proliferator-activated receptor-γ (PPAR-γ), such as the thiazolidinediones, which enhance insulin action; dipeptidyl peptidase-4 (DPP-4) inhibitors which inhibit the degradation of GLP-1 and α-glucuronidase inhibitors which interfere with gut glucose production. However, there are some deficiencies associated with these treatments. For example, sulphonylureas and insulin injections can be associated with hypoglycemia and weight gain. Responsiveness to sulphonylureas is often lost over time. An increased relative risk of pancreatic cancer and to a lesser extent other neoplasms has been linked to the use of DPP-4 inhibitors. Gastrointestinal problems are observed with metformin and α-glucosidase inhibitors. Finally, PPAR-γ agonists may cause increase weight and edema.
The present invention aims to address the needs for new treatment methods, compounds and pharmaceutical compositions for treating patients with diabetes and for treating patients with one or more disorders and conditions associated with abnormal levels of glucose, insulin, ketone bodies, plasma lipoprotein, triglycerides and the like.
International PCT publication WO 2014/138906 is a patent application filed previously by the present Applicant. That patent document describes compounds whose structure is related to the structure of the compounds of the present invention. However, that prior patent application is concerned with the treatment of fibrosis, not diabetes.
Additional features of the invention will be apparent from a review of the disclosure, figures and description of the invention herein.